A combined histological and microarray analysis of the white adipose tissue (WAT) of mice fed trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) was performed to better define functional responses. Mice fed t10c12 CLA for 14 days lost 85% of WAT mass, 95% of adipocyte lipid droplet volume, and 15% or 47% of the number of adipocytes and total cells, respectively. Microarray profiling of replicated pools (n = 2 per day x diet) of control and treated mice (n = 140) at seven time points after 1 to 17 days of t10c12 CLA feeding found between 2798 and 4318 transcript levels changed by 2-fold or more. Transcript levels for genes involved in glucose and fatty acid import or biosynthesis were significantly reduced. Highly expressed transcripts for lipases were only moderately reduced suggesting lipolysis and fatty acid export continued to occur. Increased levels of mRNAs for two key thermogenesis proteins, uncoupling protein 1 (UCP1) and carnitine palmitoyltransferase 1, may have increased energy expenditures. Significant reductions of mRNAs for major adipocyte regulatory factors, including PPAR, SREBP1, CAAT/enhancer binding protein, and Lipin 1 were correlated with the reduced transcript levels for key metabolic pathways in the WAT. A prolific inflammation response was indicated by the 2- to 100-fold induction of many cytokine transcripts, including those for IL-6, IL1, TNF ligands, and CXC family members, and an increased density of macrophages. The combination of cell loss, increased energy expenditure, and transport of lipids out of the adipocytes may account for the cumulative mass loss observed.